Osteopathic Family Physician (2013) 5, 116–122

Migraine: Burden of disease, treatment, and prevention

Natasha N. Bray, DO,a Aaron Heath, DO,b Julietta Militello, DOb

From aNova Southeastern University, College of Osteopathic Medicine, Fort Lauderdale, FL; and bBroward Health/Broward Health Medical Center, Fort Lauderdale, FL

KEYWORDS: Abstract are perhaps the most studied of the headache syndromes secondary to the high ; incidence and have significant effect on the quality of life of those suffering from this condition. Headache Despite the high prevalence of migraines, an estimated two-thirds of sufferers either have never consulted a doctor or have stopped doing so. Therefore, it is an underdiagnosed and undertreated condition. The prevalence of migraine attacks is estimated to be 17% in women and 6% in men each year. Evidence-based guidelines for both the immediate treatment as well as preventive therapy have been established. These guidelines outline several management strategies for migraine headaches, including immediately aborting the migraine at the onset of headache, controlling the pain once it has fully evolved, and prophylactic therapy. Abortive treatment should be initiated as soon as an or other warning sign is noted. Patient education plays an integral role in any management plan. Headache journals may help patients identify and avoid migraine triggers and document the response to therapeutic intervention. Physicians must be aware of warning signs that may reflect more severe underlying pathology and when neuroimaging, consultation, and hospitalization are warranted. Published by Elsevier Inc.

Migraine prevalence and disease burden those older than 60 years of age (Figure 1). In both men and women, prevalence is significantly higher in whites than in The World Health Organization has estimated that over 300 blacks.3 million people worldwide suffer from migraines. The The World Health Organization lists severe migraines American Migraine Prevalence and Prevention study along with quadriplegia, psychosis, and dementia, as one of estimates that the prevalence of migraine attacks is 17% in the most disabling chronic disorders.4 Migraines constitute women and 6% in men each year.1 In the United States, the approximately 16% of the primary headaches. Approx- ratio of females to males suffering from migraines is 2:1.2 In imately 90% of the patients who experience migraines have childhood, migraines affect boys and girls equally. This moderate to severe pain, 75% have decreased ability to trend continues until puberty, when the predominance shifts function during their headache attacks and 33% require bed to women. Peak incidence of migraines occurs between the rest during an attack.1 ages of 30 and 39. Approximately 30% of the people in this The American Migraine Prevalence and Prevention study age range are affected by migraines, of which 24% are of more than 160,000 patients found that a large majority of women and 7% men. Prevalence of migraines is lowest in patients who suffer from migraine headaches had 1-4 headaches per month (62.7%). About 54% of the patients Corresponding author: Natasha N. Bray, DO, Nova Southeastern reported severe impairment or need for bed rest during University, College of Osteopathic Medicine, 3200 S. University Drive, attacks and only about 7% of the patients reported no Fort Lauderdale, FL 33328. 1 E-mail address: [email protected] significant impairment during episodes.

1877-573X/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.osfp.2013.01.004 Bray et al. Migraine 117

Migraine Prevalence Based on Age and Sex 30

25 24.4 22.2 20 17.3 15 16 %

10 7.4 6.4 6.5 5 5 5 5 4 1.6 0 12 to 17 18 to 29 30 to 39 40 to 49 50 to 59 >60

Females Males

Figure 1 Prevalence of migraine headaches in the United States based on age and sex. Peak incidence of migraines occurs between the ages of 30 and 39. Prevalence is lowest in those older than 60 years of age. Adapted with permission from: Lipton et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68;343.1

Of migraine sufferers, approximately 10.8% of the chocolate. Nitrates and nitrites, monosodium glutamate, patients report 1 attack per week, whereas 14.4% report aspartate, dairy products, and fatty foods; 1 or more per week.2 Onset of pain is usually gradual,  sudden drop in estrogen levels associated with menses, followed by a crescendo pattern with slow but ultimately a pregnancy, and oral contraception; complete resolution. Mean duration of headache is 24 hours.  stress; The majority of patients report unilateral migraines that are  infections, especially in the head and neck; associated with pulsatile pain, light sensitivity, sound sensi-  trauma or surgery; tivity, and nausea. Approximately 60%-70% of the migraine  medications; sufferers report a prodrome, whereas 20% experience an aura  ; prior to headache attack2 (Table 1). Prodromes, as opposed to  changes in weather or climate; auras, consist of the occurrence of euphoria, depression,  strong odors including cigarette smoke and pollutants; and fatigue, hypomania, food cravings, dizziness, cognitive slow-  irregular sleep habits, bright sunlight, or flickering lights. ing, or asthenia that occurs up to 24 hours before headache. Migraine therapy

Migraine triggers The American Academy of Family Physicians, the Amer- ican College of Physicians-American Society of Internal Migraines often have a triggering event. A headache diary helps Medicine, and the American College of Neurology have to identify factors that may precipitate migraines. Common migraine triggers include but are not limited to the following6,7: established guidelines for the management of migraine headaches.8,9 Though these guidelines differ in some  Diet, caffeine excess, or withdrawal and foods that respect, nonsteroidal anti-inflammatory drugs (NSAIDs) contain phenylethylamines, tyramines, and xanthines are uniformly recommended as first-line therapy. In those including aged cheeses, red wine, beer champagne, and patients who fail to respond to NSAIDs or combination analgesics including plus acetaminophen and caffeine, Table 1 Common migraine symptoms a migraine-specific medication (, Migraine symptoms Total (%) [DHE]) should be recommended. There are several strategies in approaching the treatment Pulsatile pain 85 of migraine headaches: immediately aborting the migraine at Unilateral pain 60 onset of headache, controlling the pain once it has fully Same side always affected 20 evolved, and prophylactic therapy. Light sensitivity 80 Therapeutic considerations in tailoring medication regi- Sound sensitivity 76 men include side effects, comorbidities, pregnancy, and Nausea 73 route of administration. Prodrome 60-70 Aura 20 Migraine nonspecific therapy Adapted with permission from: Lipton RB et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41:646-657.2 Abortive treatment should be initiated as soon as an aura, prodrome, or pain is noted. 118 Osteopathic Family Physician, Vol 5, No 3, May/June 2013

NSAIDs are indicated as the first-line treatment of choice preparation. Caution should also be used with for migraine attacks because of safety, wide availability, selective serotonin reuptake inhibitors (SSRIs) and triptans tolerability, and low side-effect profile. Strong evidence because of the increased risk of serotonin syndrome. exists for the treatment of acute migraine with the NSAIDs DHE 45 is a potent cranial and peripheral vasoconstric- and the combination of acetaminophen plus aspirin and tor. It is available in IV, intramuscular, subcutaneous, and caffeine.9 intranasal forms. The IV form is usually administered in In patients who present with migraine accompanied by combination with an antiemetic drug (ie, metoclopramide). nausea and vomiting, a nonoral route of administration is Intranasal DHE 45 has also been safe and effective as preferred and antiemetics should be considered. Such monotherapy in the short-term treatment of migraines. DHE therapies include intravenous (IV) metoclopramide, IV or 45 is contraindicated in patients with ischemic heart disease, intramuscular prochlorperazine. IV diphenhydramine is hypertension, in combination with MAOI, and in the sometimes given in conjunction with these drugs to prevent elderly.15 akathisia and acute dystonic reactions. Oral antiemetics should not be considered as monotherapy.8,9 In severe migraine, rescue medications including Migraine preventive therapy opioids and butalbitol may be effective. Short-term therapy All patients suffering from migraines should be evaluated for with any of these regimens should be limited to a use of preventive therapy. Despite the large number of maximum of 2 times per week, as overuse of these patients that would benefit from preventative therapy, only a medications has been associated with drug-induced head- small percentage of patients receive it. It is believed that 40% ache. In these patients preventive therapy should be 10 of the people who get migraines would benefit from considered. Although commonly prescribed, there are preventative medication, yet only 12.4% of the adults with few studies documenting the effectiveness of opioids for 16 migraines take preventative medication. Prevention begins the treatment of migraines. Because of the high potential with limiting triggers associated with the onset of migraines for abuse and dependence, utilization of these medications as well as educating patients about their condition, available should be minimized. treatment options, and encouraging them to actively par- For patients with severe recurrent or refractory head- ticipate in their care. The goal of preventative therapy is to aches, dexamethasone in addition to standard short-term reduce the severity and frequency of headaches by 50%. migraine therapy has been shown to reduce the rate of early 11 Guidelines for the use of preventative therapy (Table 2) headache recurrence. Frequent use of adjunctive dexame- for migraines are based on an expert panel of 12 physicians thasone increases the risk of glucocorticoid toxicity and reviewing the United States headache consortium guide- should be avoided. lines. Recommendations are based on the number of Various studies found that agents given in large single headache days per month and impairment during a headache doses work better than repetitive smaller doses. Many oral attack. Level of impairment is categorized as severe agents may be ineffective because of poor absorption 12 impairment if patients are unable to function or require secondary to migraine-induced gastric stasis. bed rest, some impairment if patients are able to function, but with reduced performance, or no impairment if patients are able to function normally.1 Migraine-specific therapy Clinical guidelines differ as to when it is appropriate to start migraine preventive therapy. Other generally accepted The introduction of serotonin 1B1D agonists (triptans) has indications include 2 or more attacks per month that produce revolutionized therapy. They are considered to be specific disability lasting 3 or more days per month; contra- therapies for migraines because of their mechanism of indications to, or failure of abortive treatments; the use action. They inhibit the release of vasoactive peptides, of abortive medication more than twice per week; the promote vasoconstriction, and block pain pathways in the presence of uncommon migraine conditions, including brainstem. They also act in the descending brainstem pain hemiplegic migraine, migraine with prolonged aura, or modulation pathways and therefore inhibit dural nocicep- 10 13 migrainous infarction. Severely impaired quality of life, tion. There is good evidence demonstrating the efficacy in business duties or school attendance, as well as frequent, management of acute migraine headache with the following 14 long or uncomfortable auras may also be indications triptans. 17 that initiation of preventive therapy is appropriate Triptans have provided migraine sufferers a quick and (Tables 3–5). effective treatment modality that can be used several times per month with a minimal side-effect profile. It is recommended that triptans should be avoided in patients Medications with established efficacy in with uncontrolled hypertension, pregnancy, or ischemic migraine prevention14 heart disease. Because of the risk of serotonin syndrome, triptans are contraindicated with concomitant monoamine Level A evidence: Medications with established efficacy oxidase inhibitors (MAOI) and within 24 hours of the use of (42 class I trials) Bray et al. Migraine 119

Table 3 medications Class Notes Antiepileptic Common adverse effects: weight gain, hair loss, Name Route Notes drugs tremor, and teratogenic potential Divalproex Amlotriptan Tabs Recommended for children sodium over 12 years of age Sodium Particularly useful in patients with prolonged or Tabs 418 years of age, valproateà atypical migraine aura, benefits seen within metabolized first 4 weeks by cytochrome P450 Topiramateà Common side effects: paresthesia, tiredness, GI Fovatriptan Tabs 418 years of age disturbance Tabs 418 years of age, b- Blockers Common adverse effects: dizziness, fatigue, and Caution: renal or hepatic depression13 impairment Metroprolol Tabs/ODT 418 years of age, Propanolol Caution: concomitant propanolol use Triptans SQ Fastest onset of action For menstrually related migraine Nasal Side effect: unpleasant taste Tabs 418 years of age, GI, gastrointestinal. n Caution: hepatic Considered first-line therapy. impairment Tabs/ODT/ 418 years of age, Nasal Caution: hepatic Table 2 Migraine diagnostic criteria impairment Diagnostic criteria for migraine without aura SQ, subcutaneous. 1. At least 5 attacks fulfilling the criteria below. 2. Headache attacks lasting 4-72 hours. 3. Headache has at least 2 of the following characteristics: Therearecurrentlyonly5FoodandDrugAdministration– A. Unilateral location approved medications for the prevention of migraine headaches. B. Pulsating quality These include , timolol, , , and C. Moderate or severe pain intensity (no longer available in the United States).14 D. Aggravation by or causing avoiding of routine activity (ie, walking) b- Blockers have consistently been shown to be effective 4. During headache at least 1 of the following: in the prevention of migraines. Use should be limited in A. Nausea or vomiting or both patients with erectile dysfunction, peripheral vascular B. Photophobia or phonophobia disease, bradycardia, and hypotension. Caution is advised 5. Not attributed to another disorder. in patients with asthma and diabetes mellitus. There is little evidence supporting the use of calcium channel blockers, Diagnostic criteria for migraine with typical aura angiotensin-converting-enzyme inhibitors, and angiotensin- 1. At least 2 attacks fulfilling the criteria below. receptor blockers in migraine prevention. 2. Aura consisting of at least 1 of the following but no motor Tricyclic , particularly , have weakness: A. Fully reversible visual symptoms including positive been shown to be probably effective in migraine prevention features (ie, flickering lights, spots or lines) or negative in various studies. There is limited evidence of moderate features (ie, loss of vision) or both efficacy of fluoxetine, a SSRI; however, there is no evidence 10 B. Fully reversible sensory symptoms including positive of efficacy for other SSRIs in migraine preventive therapy. features (ie, pins and needles) or negative features (ie, If an SSRI is being considered for migraine preventive numbness) or both therapy, physicians must be aware of the potential for C. Fully reversible dysphasic disturbance At least 2 of the following: 3. A. Homonymous visual symptoms or unilateral sensory Table 4 Acute therapy symptoms or both Nonspecific pain management Migraine-specific treatment B. At least 1 aura symptom develops gradually over greater than 5 minutes or different aura symptoms occur in NSAIDs Triptans succession over greater than 5 minutes or both Acetaminophen DHE 45 C. Each symptom lasts greater than 5 minutes and less Opioids than 60 minutes Barbiturate 4. Headache fulfilling criteria for migraine without aura begins Antiemetics during the aura or follows the aura within 60 minutes. Metoclopramide 5. Not attributed to another disorder. Chlorpromazine Prochlorperazine International Headache Society ICHD-II Diagnostic criteria for migraine headaches.5 Corticosteroids 120 Osteopathic Family Physician, Vol 5, No 3, May/June 2013

Table 5 Guidelines for the use of preventative therapy in prophylactic agents are used for the treatment of chronic migraine headaches migraine, including b-blockers, topiramate, and valproic acid. Second-line agents include type A, Prevention should be offered  Migraine patients reporting 6 or more days of headache calcium channel blockers, fluoxetine, , and SSRIs. per month It is advised to start medication at the lowest possible  Four or more days of headache with at least some dose and increase gradually, allow for an appropriate trial impairment period before deeming a medication ineffective, and avoid  Three or more days of headache with severe impairment or overuse. When choosing an agent it is important to factor a requiring bed rest patient’s comorbidities, psychiatric disorders, sleep disor- ders, and child-bearing status. Prevention should be considered With appropriate preventive therapy, approximately 50%  Migraine patients with 4-5 number of migraine days per of the patients will have a 50% reduction in frequency of month with normal functioning migraines after 3 months. Complete eradication of head-  Three days of migraine per month with some impairment aches in chronic migraine sufferers is unlikely. The primary  Two days of migraine with severe impairment goal of preventive therapy should be to reduce the frequency and severity of headaches. As such it is important for Prevention is not indicated physicians to discuss and set realistic goals for the treatment  Migraine patients with less than 4 days of headache per of chronic migraines. month and no impairment  Subjects with no more than 1 day of headache per month regardless of impairment The role of osteopathic medicine in the Adapted with permission from: Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive treatment and prevention of migraines therapy. Neurology. 2007;68;343.1 Several studies have looked into the role of osteopathic manipulative therapy (OMT) and spinal manipulative therapy serotonin syndrome, a potentially life-threatening drug (SMT) and their role in treatment and prevention of migraines. interaction. SSRIs are contraindicated with MAOI. Other Although some studies have shown no benefit, others have drug interactions associated with an increased risk of shown that OMT may play a role in the treatment of migraines.22 serotonin syndrome are triptans, tricyclic antidepressants, Schabert et al. examined the use of OMT in an opioids, and antiemetics to name a few.18 osteopathic family medicine clinic and its effect on the cost Time-release DHE has consistently shown efficacy in of treating patients with migraines compared with an migraine prevention; however, there is limited data with allopathic clinic in which migraine sufferers did not receive respect to adverse effects. OMT. Average cost per patient visit was approximately Alternative therapy 50% less at the osteopathic clinic compared with the allopathic clinic. This difference was attributed to fewer Several supplements and herbs have been evaluated for the medications prescribed in the osteopathic clinic resulting in prevention of migraines. Butterbur (Petasites hybridus root), lower average medication cost. OMT techniques in this coenzyme Q10, magnesium oxide, and riboflavin have all study included counterstrain, high-velocity, low-amplitude shown some benefit in migraine prevention, however data technique, ligamentous articular strain technique, muscle are limited.17 energy, and osteopathic cranial techniques.23 Randomized controlled trials have shown that relaxation Voigt et al. examined 42 female patients with a known training, thermal with relaxation training, diagnosis of migraines in a randomized controlled trial to electromyogram biofeedback, and cognitive behavioral examine the efficacy of OMT in . The therapy reduce migraine frequency by 30%-50%. These technique of OMT was dependent on the particular data suggest that behavioral therapies can be as effective as osteopathic findings and included manual, visceral and many pharmacologic treatments.19 cranial techniques. Migraine sufferers who received OMT Proper sleep hygiene is also very important. Restful sleep reported decreased pain intensity, reduction in the number of decreases irritability in the brain, and therefore may migraine days and improved health-related quality of life.24 decrease the frequency and severity of migraine. In another analysis, Keays et al. reviewed a trial comparing migraine prophylaxis with amitriptyline vs Treatment of chronic migraine SMT, a component of osteopathy. A total of 218 patients were randomized to receive either SMT for 2 months or oral Though classification of chronic migraine varies, the most amitriptyline. A headache index, used to measure daily pain commonly accepted general definition by the International intensity, was equivalent in both groups in the last 4 weeks Headache Society is 15 or more days of headache per month of treatment. Though statistically nonsignificant, there was a for at least 3 months.20,21 The treatment of chronic migraine trend toward a lower headache index in the group that should be focused on prevention. Many of the same received SMT compared with the amitriptyline group. Also Bray et al. Migraine 121 of note, 10% of the patients receiving amitriptyline with- aura and increased risk for ischemic stroke, angina, and other drew from the study secondary to side effects, whereas no ischemic vascular events including myocardial infarction. In adverse effects were reported in the SMT group.25 this study, migraine without aura was not shown to be associated with an increased risk for cardiovascular disease.26 Investigational agents A cohort study in healthy men did not include information regarding aura but did show that those suffering Several drug classes are being investigated for their use in from migraines had a higher risk for cardiovascular events the treatment of acute migraine headaches. These drugs than those without migraines, but not associated increased include calcitonin gene-related peptide receptor antagonists risk of ischemic stroke.27 and serotonin 1F receptor agonists. However because of the MacClellan et al. studied women with probable migraine high number of adverse effects, most notably hepatotoxicity, with visual aura and similarly found an increased associa- some studies have been halted, and therefore continued tion with ischemic stroke, particularly among women research is necessary.12 without other medical conditions associated with stroke. Risk factors including smoking and oral contraceptive use Neuroimaging and specialist consultation increase the risk of migraine with aura.28 Migraine with aura has also been associated with an Neuroimaging is not always necessary in patients with unfavorable vascular risk profile measured by the Framing- migraine headaches. The American Academy of Neurology ham risk score for coronary heart disease. It is associated suggests neuroimaging in the following patients with with an increased risk of ischemic stroke among women nonacute headaches: with low vascular risk profiles, whereas it is associated with an increased risk of myocardial infarction among women  patients with an abnormal finding on neurologic with high vascular risk scores.29 examination; A systemic review and meta-analysis of migraine and  patients with atypical headache features; cardiovascular disease by Schurks et al. showed a 2-fold  headaches that do not fulfill the strict definition of increased risk for ischemic stroke in women suffering from migraine or other primary headache disorder; and migraine with aura. This review again supported an  immunocompromised patients. increased risk among women as compared with men, as Physicians should have a low threshold for neuroimaging well as an increased risk in women less than 45 years of age, testing in patients who present with a sudden onset severe smokers, and the use of oral contraception. This review did headache. These patients warrant neuroimaging because of not however show an overall increased risk or association the suspicion of subarachnoid hemorrhage and require between migraines with or without aura and myocardial immediate hospital evaluation. infarction.30 In most patients, a computed tomography scan of the head Information with regard to history of migraine and with and without contrast is sufficient. A magnetic resonance vascular risk status might help to identify women at (MR) imaging is indicated when posterior fossa lesions or increased risk for specific future cardiovascular disease cerebrospinal fluid leaks are suspected. Additional imaging, events.29 Migraine with aura has been consistently asso- including MR angiography and MR venography, are ciated with ischemic stroke. This risk appears to be indicated when arterial or venous lesions, respectively, are amplified in younger women, smokers, and with the use suspected. No other diagnostic tests are typically necessary.8 of oral contraceptives. Consequently, young women who Practioners should prompt referral for further investiga- suffer from these types of headaches should be counseled tion or specialist consultation in the following8: extensively regarding smoking cessation and birth control other than oral contraceptives should be considered.30  progressive neurologic symptoms;  a change in headache pattern in patients over 50;  sudden onset severe “thunderclap” headache; Long-term complications  postural headaches;  new onset headache in patients with HIV or cancer; The International Headache Society recognizes the follow-  severe headaches that wake patients from sleep; ing as potential long-term complications of migraine  headaches caused by physical exertion; headaches31:  jaw claudication; and  fever and neck stiffness.  chronic migraines;  status migrainosus (headaches lasting over 72 hours);  persistent aura without infarction; Risk of cardiovascular disease  migrainous infarction; and  migraine-induced seizure. Migraine with aura has been associated with an adverse cardiovascular risk profile. In a large prospective cohort of Symptoms may last for days, weeks, years, or in some women, Kurth et al. showed an association of migraine with cases leave permanent neurologic deficit. 122 Osteopathic Family Physician, Vol 5, No 3, May/June 2013

Conclusions 11. Colman I, Friedman BW, Brown MD, et al: Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised The proper evaluation and treatment of migraine headaches controlled trials for preventing recurrence. Br Med J. 2008;336:1359 is pivotal for practitioners to understand. Patients must be 12. Bajwa Z, Sabahat A. Acute treatment of migraine in adults. In: educated about their condition and encouraged to participate UpToDate, Swanson, JW (Ed), UpToDate, Waltham, MA, 2012. 13. Schulman EA, Cady RK, Henry D. Effectiveness of sumatriptan in reducing in their care. All the available treatment options should be productivty loss due to migraine: results of a randomized, double-blind, discussed and realistic goals should be established. Engaged -controlled, . Mayo Clin Proc. 2000;75:782 patients are more likely to provide vital input regarding their 14. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman treatment plan allowing the physician to better understand E; Quality Standards Subcommittee of the American Academy of and accommodate patient goals. Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine Lifestyle changes with the help of headache diaries assist prevention in adults: report of the Quality Standards Subcommittee patients in avoiding migraine triggers. Patients suffering of the American Academy of Neurology and the American Headache from migraines should be thoroughly screened and eva- Society. Neurology. 2012;78(17):1337–1345. luated for the need of preventive therapy. Guidelines have 15. Colman I, Brown MD, Innes GD. Parenteral dihydroergotamine for been established to aid practitioners in the treatment and acute migraine headache: a systemic review of the literature. Ann Emerg Med. 2005;45:393 prevention of migraines. 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